Introduction to Biomanufacturing

1st Edition November 2011

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Editor in Chief: Margaret Bryans Chapter Authors Introduction: Sonia Wallman Facilities: Bryan Shingle Metrology: Gene Kernan Validation: Patrick Sheehy, Tom Burkett Environmental, Health, and Safety (EHS): John Piampiano Operational Excellence: Martha Matthews Quality Assurance: Frank Hallinan, Ron Hudcosky, Cynthia Sarnoski, Kevin Lampe Microbiological Control: John Hasyn, Frank Hallinan, Jim Labore, Linda Rehfuss Quality Control Biochemistry: Mary Harne, Zhenhong Li Production: Upstream Processing: Olga Mollin, Jane Flanagan Production: Downstream Processing: Paul O'Neil Process Development: Eszter Birck-Wilson Reviewers/Additional Contributors Deb Audino Sheila Byrne Niall Carolan A. Stephen Dahms Cindy Dove Lara Dowland Tim Dubuque Mike Fino James Hewlett Joanna Kile Mary Jane Kurtz Ben Locwin Joseph Lingle Duncan Ross Bill Woodruff Technical Editors: John Dees

John Fuselier

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Introduction to Biomanufacturing, 1st Edition Foreword Today is a time of unparalleled excitement in the world of biopharmaceuticals. What were largely unknown to the general public only 20 years ago, biologically derived drugs, have become enormously popular. The National Institutes of Health and IMS Health have both published studies suggesting that biologics will comprise one-fifth of the total drug market by 2015. The timeline of biomanufacturing is very discontinuous. Though humans used principles of biotechnology since they first saved the seeds of high-producing plants (natural selection), it was really not for about the next 9000 years that this knowledge advanced appreciably. There is a complex world of microbes all around us. The empirical research to first identify germs and their causal relationship with disease was provided by Louis Pasteur. He famously stated “La génération spontanée est une chimère,” (The spontaneous generation [of microorganisms] is a fantasy); this idea made clear that microorganisms do not come from nothing. This can be rephrased in Latin as “Omne vivum ex vivo,” (all life is from life). This was an incredible paradigm shift, and since Pasteur’s innovative ideas, humanity has worked incredibly quickly to understand, modify, and harness the microbiological world to improve our lives. What we do as scientists and thought leaders in this industry is to ensure that our future continues to bring us a substantial number of rich insights and valuable technologies. The work we do speaks a great deal about our desire to achieve something bigger for humanity; the lives we lead have purpose, and this book is testament to the fact that part of that purpose is improving our collective health and well-being through the application of good science. The book that you hold is a compendium of a tremendous body of knowledge, distilled into its most essential parts. I know of no other text that strikes such a fine balance of breadth and depth in its contents on the topic. Not only are there theoretical and conceptual ideas about biopharmaceutical manufacturing, but also content specific to skills and abilities. It serves as a well-paced guide for beginning learners as well as a cogent reference for seasoned biotechnology professionals alike. As the industry continues to grow, we need more bright minds to keep pushing the envelope. It is my hope with this book that a new generation of students can be inspired and familiarize themselves with the theories, principles, and vernacular of biopharmaceutical production and all that it entails. I can think of no others more appropriate to develop this reference text than Sonia Wallman and the NBC2 team; Sonia has worked tirelessly to open the eyes of students to the biopharmaceutical sciences, and in the process has earned the admiration and respect of countless people. On behalf of Sonia and the team, I hope you find this text an engaging and rewarding read. Ben Locwin Portsmouth, New Hampshire June 2012

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Table of Contents

CHAPTER 1 INTRODUCTION ................................... 1 BIOPHARMACEUTICAL MANUFACTURING (BIOMANUFACTURING) .......................................... 2

Production of the first biopharmaceutical ................................................................................ 2 Production of biopharmaceuticals from 1982 to the present ................................................... 5

DRUG DISCOVERY, CLINICAL TRIALS, AND COMMERCIAL PRODUCTION .................................. 7

Discovery research ..................................................................................................................... 8 Process development and scale-up ......................................................................................... 11 Manufacturing .......................................................................................................................... 11

BUILDING AND STAFFING A BIOPHARMACEUTICAL PRODUCTION FACILITY ............................. 13

TEXTBOOK ORGANIZATION ....................................................................................... 17

ENGINEERING UNIT OVERVIEW ................. 21 CHAPTER 2 FACILITIES ........................................ 27 OBJECTIVES .......................................................................................................... 28

TERMS ................................................................................................................ 29

INTRODUCTION TO FACILITIES .................................................................................... 30

Facility design and regulatory framework ............................................................................... 31 Functional areas/unit operations ............................................................................................. 36

MATERIAL AND PERSONNEL FLOW ............................................................................. 43

ROOM CLASSIFICATIONS .......................................................................................... 44

FACILITY SECURITY AND ACCESS CONTROLS .................................................................. 51

PROCESS EQUIPMENT, INSTRUMENTATION, AND CONTROL SYSTEMS .................................. 52

Vessels ...................................................................................................................................... 53 Piping ........................................................................................................................................ 53 Valves ....................................................................................................................................... 53 Motors ...................................................................................................................................... 54 Pumps ....................................................................................................................................... 54 Compressors ............................................................................................................................. 54 Fans .......................................................................................................................................... 54 Reactors .................................................................................................................................... 54

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Columns .................................................................................................................................... 55 Boilers ....................................................................................................................................... 55 Laminar flow hoods .................................................................................................................. 55 Filters ........................................................................................................................................ 56 Centrifuges ............................................................................................................................... 56 Autoclaves ................................................................................................................................ 56 Refrigerators/freezers .............................................................................................................. 57 Conveyors ................................................................................................................................. 57 Filling, sealing, packaging, and labeling machines ................................................................... 57 Instrumentation and process control ...................................................................................... 57

PROCESS UTILITY SYSTEMS ....................................................................................... 59

FACILITY SUSTAINABILITY ......................................................................................... 61

STANDARD PROCESS DOCUMENTS AND DRAWINGS ........................................................ 61

CHECK YOUR KNOWLEDGE ....................................................................................... 63

ACTIVITIES ........................................................................................................... 64

CHAPTER 3 METROLOGY ..................................... 65 OBJECTIVES .......................................................................................................... 66

TERMS ................................................................................................................ 67

INTRODUCTION ..................................................................................................... 68

History of metrology ................................................................................................................ 69 The progress of measurements ............................................................................................... 70

METROLOGY FUNDAMENTALS .................................................................................. 72

Units of measurement ............................................................................................................. 73 Base units .............................................................................................................................. 74 Supplemental units ............................................................................................................... 75 Derived units ......................................................................................................................... 75

Standardization and calibration ............................................................................................... 75 Accuracy and uncertainty ..................................................................................................... 76 Specifications and tolerances ............................................................................................... 77

CLASSIFICATION OF MEASUREMENT ERRORS AND THEIR SOURCES ...................................... 77

MEASUREMENT TRACEABILITY .................................................................................. 78

Test Uncertainty Ratio (TUR)/Test Accuracy Ratio (TAR) ........................................................ 79 Standardization ........................................................................................................................ 79 Instruments and test equipment ............................................................................................. 79

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METROLOGY PROGRAMS ......................................................................................... 79

Adequacy of calibration equipment and standards ................................................................. 82 Audit requirements .................................................................................................................. 83 Calibration procedures ............................................................................................................. 83 Calibration intervals ................................................................................................................. 83 Calibration quality .................................................................................................................... 84 Calibration scheduling .............................................................................................................. 88 Computer software validation ................................................................................................. 88 Environmental controls ............................................................................................................ 90 Labels ........................................................................................................................................ 90 Measurement traceability ........................................................................................................ 91 Personnel requirements .......................................................................................................... 92 Records ..................................................................................................................................... 93 Supplier control ........................................................................................................................ 95 Metrology program summary .................................................................................................. 96

CALIBRATION IN A BIOMANUFACTURING ENVIRONMENT .................................................. 96

CHECK YOUR KNOWLEDGE ....................................................................................... 99

ACTIVITIES ......................................................................................................... 100

CHAPTER 4 VALIDATION ................................... 101 OBJECTIVES ........................................................................................................ 102

TERMS .............................................................................................................. 103

WHAT IS VALIDATION? ......................................................................................... 107

A validation example .............................................................................................................. 108 Documented evidence ........................................................................................................... 110 The need for validation .......................................................................................................... 112

THE VALIDATION LIFECYCLE .................................................................................... 115

THE VALIDATION PROGRAM ................................................................................... 117

Validation policies .................................................................................................................. 117

A RISK-BASED APPROACH TO VALIDATION ................................................................. 121

Risk analysis ............................................................................................................................ 121 Risk assessment ...................................................................................................................... 124

VALIDATION OF FACILITIES, EQUIPMENT, AND UTILITIES ................................................ 129

Stages of qualification/validation .......................................................................................... 129 Formation of a project team ............................................................................................... 129

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Requirements phase ........................................................................................................... 130 Design Qualification ............................................................................................................ 130 Risk assessment/impact assessment .................................................................................. 130 Construction ........................................................................................................................ 131 Validation planning ............................................................................................................. 131 Commissioning .................................................................................................................... 132 Installation Qualification and Operational Qualification (IQ/OQ) ...................................... 133 Performance Qualification (PQ) .......................................................................................... 134 Final report .......................................................................................................................... 134 Related programs/Process Validation (PV) ......................................................................... 135 Plant release and start-up ................................................................................................... 135 Periodic review, change control, and revalidation ............................................................. 135

VALIDATION OF ANALYTICAL METHODS AND EQUIPMENT .............................................. 136

Analytical equipment qualification ........................................................................................ 136 Analytical method qualification ............................................................................................. 138

COMPUTERIZED SYSTEMS AND SOFTWARE VALIDATION ................................................. 144

Computerized System Architecture (CSA) ............................................................................. 145 Key elements of Computerized System Validation ................................................................ 146

PROCESS VALIDATION ........................................................................................... 149

CLEANING VALIDATION ......................................................................................... 154

Cleaning validation limits ....................................................................................................... 154 Product cleanability ............................................................................................................... 155 Product introduction .............................................................................................................. 155 Cleaning processes ................................................................................................................. 155 Dirty Hold Time (DHT) ............................................................................................................ 155 Clean Hold Time (CHT) ........................................................................................................... 156 Cleaning training .................................................................................................................... 156 Analytical equipment and method validation ....................................................................... 156 Document hierarchy .............................................................................................................. 156 Cleaning validation protocols ................................................................................................. 157 Development protocols ......................................................................................................... 157 Validation protocols ............................................................................................................... 157 Standard Operating Procedures (SOP) ................................................................................... 158 Validation execution sequencing ........................................................................................... 158

CHANGE CONTROL AND RE-VALIDATION .................................................................... 158

OUT-OF-SPECIFICATION RESULTS AND FAILURE INVESTIGATIONS ..................................... 160

CHECK YOUR KNOWLEDGE ..................................................................................... 161

ACTIVITIES ......................................................................................................... 163

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CHAPTER 5 ENVIRONMENTAL, HEALTH, AND SAFETY (EHS).......................................... 165 OBJECTIVES ........................................................................................................ 166

TERMS .............................................................................................................. 167

ENVIRONMENTAL, HEALTH, AND SAFETY PROGRAMS IN BIOMANUFACTURING ........................................................................ 169

REGULATORY REQUIREMENTS AND GUIDANCE ............................................................ 172

OSHA ...................................................................................................................................... 173 EPA ......................................................................................................................................... 174 Other guidance ....................................................................................................................... 175 Centers for Disease Control and Prevention (CDC) ............................................................... 176 NIOSH ..................................................................................................................................... 176 Fire and building codes .......................................................................................................... 177 Hazardous materials/dangerous goods transportation ......................................................... 178 ISO .......................................................................................................................................... 178 International standards .......................................................................................................... 179 Non-regulated industry standards ......................................................................................... 179

HAZARD RECOGNITION, IDENTIFICATION, ANALYSIS, AND RISK ASSESSMENT ...................... 180

Recognition and identification ............................................................................................... 180 Hazard analysis and risk assessment ..................................................................................... 185

HAZARD PROTECTION AND CONTROL STRATEGIES ........................................................ 189

BIOMANUFACTURING-SPECIFIC PROTECTIVE MEASURES ................................................ 193

Facility design ......................................................................................................................... 194 Equipment .............................................................................................................................. 194 Protective practices and techniques ...................................................................................... 198

COMPONENTS OF A BIOMANUFACTURING EHS PROGRAM ............................................. 200

Accident reporting and investigation ..................................................................................... 200 Biological and chemical inventory ......................................................................................... 200 Bloodborne pathogens ........................................................................................................... 201 Communication ...................................................................................................................... 201 Confined space entry ............................................................................................................. 201 Emergency Action Plans (EAP) ............................................................................................... 201 Employee responsibilities ...................................................................................................... 202 Ergonomics and human factors ............................................................................................. 202 Fire prevention/protection .................................................................................................... 202

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Fleet safety ............................................................................................................................. 203 Hazard Communication (HazCom) ......................................................................................... 203 Hearing protection ................................................................................................................. 203 Industrial hygiene ................................................................................................................... 204 Lockout-Tagout (LOTO) .......................................................................................................... 204 Machinery safeguarding ........................................................................................................ 204 Management Of Change (MOC)............................................................................................. 205 Materials handling and management .................................................................................... 205 Measures to track performance ............................................................................................ 205 Natural disaster response and recovery ................................................................................ 205 Personal Protective Equipment (PPE) .................................................................................... 205 Process safety ......................................................................................................................... 206 Recordkeeping ....................................................................................................................... 206 Respiratory protection ........................................................................................................... 206 Security ................................................................................................................................... 206 Training ................................................................................................................................... 206 Waste management ............................................................................................................... 207

CHECK YOUR KNOWLEDGE ..................................................................................... 208

ACTIVITIES ......................................................................................................... 209

REFERENCES ....................................................................................................... 209

CHAPTER 6 OPERATIONAL EXCELLENCE ................ 211 OBJECTIVES ........................................................................................................ 212

TERMS .............................................................................................................. 213

INTRODUCTION TO OPERATIONAL EXCELLENCE ............................................................ 216

Overview ................................................................................................................................ 216 Background on quality efforts and their influence on Operational Excellence ..................... 216

BUSINESS OF BIOMANUFACTURING .......................................................................... 218

WHAT IS A PROCESS? ........................................................................................... 219

Lean manufacturing ............................................................................................................... 220 What is an efficient workplace? ............................................................................................. 222 How to deploy lean improvements ........................................................................................ 225

SIX SIGMA PROCESS IMPROVEMENTS ........................................................................ 225

What is process control? ........................................................................................................ 226 What is Six Sigma?.................................................................................................................. 226 What is process variability? ................................................................................................... 228 How to get a process in control ............................................................................................. 230

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THE FUTURE OF OPERATIONAL EXCELLENCE: DEPLOYMENT CHALLENGES ............................ 236

Creating and identifying the OE culture ................................................................................. 236 Lean Six Sigma credentialing process .................................................................................... 237

CHECK YOUR KNOWLEDGE ..................................................................................... 240

ACTIVITIES ......................................................................................................... 241

QUALITY UNIT OVERVIEW ...................... 243 CHAPTER 7 QUALITY ASSURANCE ........................ 249 OBJECTIVES ........................................................................................................ 250

TERMS .............................................................................................................. 251

INTRODUCTION TO THE QUALITY ASSURANCE OF BIOPHARMACEUTICALS ............................ 253

QUALITY ASSURANCE (QA), QUALITY CONTROL (QC), AND QUALITY SYSTEMS ......................................................................................... 256

GOOD MANUFACTURING PRACTICES (GMPS) ............................................................ 258

ELEMENTS OF A PHARMACEUTICAL QUALITY SYSTEM .................................................... 262

THE RESPONSIBILITIES OF THE QUALITY UNIT .............................................................. 264

PRIMARY QA ACTIVITIES ....................................................................................... 264

Documentation review .......................................................................................................... 265 Change control ....................................................................................................................... 269 Marketing authorization ........................................................................................................ 269 Deviations ............................................................................................................................... 269

DOCUMENTATION IN PHARMACEUTICAL MANUFACTURING ............................................ 270

REGULATIONS AND REGULATORY AGENCIES ................................................................ 271

REGULATORY INSPECTIONS ..................................................................................... 274

CHECK YOUR KNOWLEDGE ..................................................................................... 278

ACTIVITIES ......................................................................................................... 279

REFERENCES…………………………………………………………………………………………………..279

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CHAPTER 8 MICROBIOLOGICAL CONTROL ...................................................... 281 OBJECTIVES ........................................................................................................ 282

TERMS .............................................................................................................. 283

FOUNDATIONS OF MICROBIOLOGY ........................................................................... 284

BACTERIA, FUNGI, AND MYCOPLASMA ...................................................................... 285

Viruses .................................................................................................................................... 287 Prions ...................................................................................................................................... 288 Microbiological control .......................................................................................................... 289

TYPES OF CONTAMINATION .................................................................................... 291

Particulate/"non-viable" contamination ............................................................................... 291 Microbial/"viable" contamination ......................................................................................... 293 Sources of contamination ...................................................................................................... 295

CONTROL OF CONTAMINANTS IN THE CLEANROOM ....................................................... 296

Control through facility design ............................................................................................... 296 Control through air supply ..................................................................................................... 297 Control through sterilization of components and equipment ............................................... 297 Control by aseptic gowning .................................................................................................... 301 Control through aseptic techniques ...................................................................................... 303 Control by cleaning and disinfection ..................................................................................... 307

ENVIRONMENTAL MONITORING .............................................................................. 312

Prerequisites for an environmental monitoring program ..................................................... 312 Components of an effective environmental monitoring program ........................................ 313 Sampling frequency ................................................................................................................ 316 Trending environmental monitoring test results ................................................................... 321 Test methodology .................................................................................................................. 322 Air monitoring ........................................................................................................................ 323 Non-viable particulate monitoring ......................................................................................... 325 Surface and equipment microbial monitoring ....................................................................... 326 Microbial monitoring of gowned personnel .......................................................................... 328 Utility monitoring ................................................................................................................... 329 Media fills ............................................................................................................................... 331 Microbial identification .......................................................................................................... 331 Utilization of information derived from environmental monitoring ..................................... 332

QUALITY CONTROL PRACTICES IN THE MICROBIOLOGY LABORATORY ................................. 334

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Quality Control of microbiological culture media .................................................................. 334 Maintenance of microbiological stock cultures ..................................................................... 336

BARRIER ISOLATION TECHNOLOGY ............................................................................ 337

CHECK YOUR KNOWLEDGE ..................................................................................... 338

ACTIVITIES ......................................................................................................... 339

CHAPTER 9 QUALITY CONTROL BIOCHEMISTRY ............................................... 341 OBJECTIVES ........................................................................................................ 342

TERMS .............................................................................................................. 343

INTRODUCTION TO QUALITY CONTROL IN THE BIOTECHNOLOGY INDUSTRY ......................... 346

INTRODUCTION TO QUALITY CONTROL BIOCHEMISTRY .................................................. 347

QUALITY CONTROL RESPONSIBILITIES & MAINTAINING A STATE OF CONTROL ............................................................................................ 347

What are QC's responsibilities? ............................................................................................. 347 The need for a state of control .............................................................................................. 348 Maintaining a state of control................................................................................................ 350 The role of Quality Control biochemistry .............................................................................. 351

BASIC OVERVIEW OF A QUALITY CONTROL FUNCTION ................................................... 353

Quality Control and Quality Management ............................................................................. 353 Specifications ......................................................................................................................... 353 Analytical methods ................................................................................................................. 357 Compendial test methods ...................................................................................................... 360 Non-compendial test methods .............................................................................................. 361

PHASES OF METHODS (DEVELOPMENT, QUALIFICATION, AND VALIDATION/POST VALIDATION) ....................................................................... 369

DATA TRENDING.................................................................................................. 370

CHECK YOUR KNOWLEDGE ..................................................................................... 372

ACTIVITIES ......................................................................................................... 372

PRODUCTION UNIT OVERVIEW ................ 373 CHAPTER 10 UPSTREAM PROCESSING .................. 379

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OBJECTIVES ........................................................................................................ 380

TERMS .............................................................................................................. 381

INTRODUCTION TO UPSTREAM PROCESSING ............................................................... 386

Overview ................................................................................................................................ 386 Cells and proteins ................................................................................................................... 386

UPSTREAM PROCESSING AREAS, EQUIPMENT, AND SYSTEMS .......................................... 388

Dispensing room .................................................................................................................... 388 CIP/SIP systems ...................................................................................................................... 390 Media preparation area ......................................................................................................... 391

CELL CULTURE/FERMENTATION ............................................................................... 393

Environment necessary for cell growth ................................................................................. 393 Cell banking ............................................................................................................................ 394 Inoculum ................................................................................................................................ 395 Role of pH in cell culture ........................................................................................................ 399 Bioreactors ............................................................................................................................. 403 Primary recovery (harvest) .................................................................................................... 417

CHECK YOUR KNOWLEDGE ..................................................................................... 422

ACTIVITIES ......................................................................................................... 422

CHAPTER 11 DOWNSTREAM PROCESSING ............. 423 OBJECTIVES ........................................................................................................ 424

TERMS .............................................................................................................. 425

INTRODUCTION TO DOWNSTREAM PROCESSING .......................................................... 426

GOALS OF THE DOWNSTREAM PROCESS ..................................................................... 428

DOWNSTREAM PROCESS UNIT OPERATIONS ............................................................... 431

Process filtration .................................................................................................................... 431 Chromatography (general) ..................................................................................................... 435 Chromatography scale-up principles ..................................................................................... 438 Viral clearance by filtration and inactivation ......................................................................... 441 Further validation/qualification of filtration media and chromatography sorbents............. 443

UNIT OPERATION PREPARATIONS ............................................................................ 444

Column packing and packed bed qualification ...................................................................... 444

PROCESS ECONOMICS AND OPTIMIZATION ................................................................. 449

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EQUIPMENT DESIGN SPECIFICATION AND PROCUREMENT ............................................... 453

EQUIPMENT PREVENTIVE MAINTENANCE ................................................................... 454

SINGLE-USE DISPOSABLE SYSTEMS ........................................................................... 455

KEY TRENDS IN THE BIOMANUFACTURING INDUSTRY ..................................................... 456

CHECK YOUR KNOWLEDGE ..................................................................................... 457

ACTIVITIES ......................................................................................................... 458

CHAPTER 12 PROCESS DEVELOPMENT ................. 459 OBJECTIVES ........................................................................................................ 460

TERMS .............................................................................................................. 461

INTRODUCTION TO PROCESS DEVELOPMENT ............................................................... 463

CHOICE OF EXPRESSION SYSTEM .............................................................................. 463

STAGES OF PROCESS DEVELOPMENT ......................................................................... 464

Process characterization ........................................................................................................ 466 Process validation .................................................................................................................. 469

VIRAL INACTIVATION AND VIRAL CLEARANCE .............................................................. 470

THE IMPACT OF PROCESS DEVELOPMENT ON UPSTREAM/DOWNSTREAM PROCESSING ................................................................... 471

UPSTREAM PROCESSING ........................................................................................ 471

Expression systems ................................................................................................................ 471 Scale-up considerations ......................................................................................................... 473 Harvest ................................................................................................................................... 474

DOWNSTREAM PROCESSING ................................................................................... 474

CHECK YOUR KNOWLEDGE ..................................................................................... 477

ACTIVITIES ......................................................................................................... 478

APPENDIX A MASTER GLOSSARY ........................ 479